In the past 3 decades, we have seen significant improvement in 1-year kidney transplant patient and graft survival rates but limited improvement in long-term outcomes. Success, to date, has largely been the result of more potent immunosuppressive therapy that permitted a de-emphasis on HLA matching in kidney allocation. Yet activation of an immune response (seen by development of acute rejection and/or new onset donor specific antibodies), continues to play a major role in late graft loss. Recent data shows that two factors associated with acute rejection, new donor specific antibody and late graft loss are epitope mismatching and medication nonadherence. Advances in genetic and protein modeling currently allow more detailed comparisons of the similarities and differences between donor and recipient HLA molecules. These new techniques are able to study epitopes (sub-sections of the molecule) rather than the entire HLA molecule, and determine whether or not there is epitope matching between the transplant donor and recipient. In independent studies we found that both epitope mismatches and subclinical (not clinically appreciated, and detected only by electronic monitoring) medication nonadherence are each associated with worse kidney transplant outcomes. Our preliminary data shows that they are independent, synergistic, correlates of late rejection and graft loss. For preparation of the R34 grant, we have assembled an international, multidisciplinary team with extensive experience in kidney transplant clinical trials, in medication nonadherence (and specifically in transplant medication nonadherence) and in translational human immunology research. The trial will be done at 8 committed North American centers. The goal of the R34 grant is to develop and finalize a proposal for a 5- year study. The goals of the 5-year grant will be: (1) to determine - n a prospective, genetically diverse real- world cohort - the independent and synergistic impact of epitope mismatch and early subclinical medication nonadherence on the development of de novo donor specific antibody, acute rejection, graft dysfunction, and graft loss; (2) to define whether specific immunodominant epitope mismatches exist irrespective of the recipient's race; and (3) to learn, in a prospective randomized controlled study of recipients with early subclinical medication nonadherence, whether intervention to improve subsequent adherence mitigates the impact of early nonadherence and/or epitope mismatches on transplant outcomes. Ours will be the first prospective study of epitope mismatching plus subclinical medication nonadherence in transplant recipients. It will be the first to determine, in those with nonadherence (a subgroup at high risk group for late rejection and graft loss), if a multicomponent intervention that is scalabe and potentially applicable to clinical use, will reduce ongoing medication nonadherence, modify the impact of early medication nonadherence (with or without epitope mismatch) and improve clinical outcomes. The results of these studies could potentially impact both kidney allocation algorithms and postransplant clinical care.